Intestinal FXR: A New Therapeutic Target for Nonalcoholic Fatty Liver Disease

1 Nat Med. 2015 Feb;21(2):159–165. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance Sungsoon Fang, Jae Myoung Suh, Shannon M. Reilly, Elizabeth Yu, Olivia Osborn, Denise Lackey, Eiji Yoshihara, Alessia Perino, Sandra Jacinto, Yelizaveta Lukasheva, Annette R. Atkins, Alexander Khvat, Bernd Schnabl, Ruth T. Yu, David A. Brenner, Sally Coulter, Christopher Liddle, Kristina Schoonjans, Jerrold M. Olefsky, Alan R. Saltiel, Michael Downes and Ronald M. Evans Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA. Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA. Department of Medicine, University of California San Diego, San Diego, California, USA. Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Federale de Lausanne, Switzerland. ChemDiv, Inc., San Diego, California, USA. Storr Liver Unit, Westmead Millennium Institute, Sydney Medical School, University of Sydney, Australia. Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California, USA. The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation, and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements